Novel asymmetric synthesis of (S)-(+)-3-(Aminomethyl)-5-methylhexanoic acid

ABSTRACT

The invention encompasses processes for the synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, (S)-Pregabalin, and intermediates of (S)-Pregabalin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. provisionalapplication Ser. Nos. 60/718,689, filed Sep. 19, 2005; 60/754,392, filedDec. 27, 2005; 60/763,593, filed Jan. 30, 2006; 60/752,434, filed Dec.20, 2005; 60/753,220, filed Dec. 21, 2005; 60/763,696, filed Jan. 30,2006; and 60/839,947, filed Aug. 23, 2006, herein incorporated byreference.

FIELD OF THE INVENTION

The invention encompasses processes for the synthesis of(S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, (S)-Pregabalin, andintermediates of (S)-Pregabalin.

BACKGROUND OF THE INVENTION

(S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, acompound having the chemical structure,

is also known as γ-amino butyric acid or (S)-3-isobutyl GABA.(S)-Pregabalin, marketed under the name LYRICA®, has been found toactivate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dosedependent protective effect on-seizure, and is a CNS-active compound.(S)-Pregabalin is useful in anticonvulsant therapy, due to itsactivation of GAD, promoting the production of GABA, one of the brain'smajor inhibitory neurotransmitters, which is released at 30 percent ofthe brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, andanxiolytic activity.

Several processes for the synthesis of (S)-Pregabalin are known. Forexample, see DRUGS OF THE FUTURE, 24 (8), 862-870 (1999). One suchprocess is illustrated in scheme 1.

In Scheme 1, 3-isobutyl glutaric acid, compound 2, is converted into thecorresponding anhydride, compound 3, by treatment with refluxing aceticanhydride. The reaction of the anhydride with NH₄OH produces theglutaric acid mono-amide, compound 4, which is resolved with(R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of(R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 5. Combining thesalt with an acid liberates the R enantiomer, compound 6. Finally, aHoffmann degradation with Br₂/NaOH provides (S)-Pregabalin. Adisadvantage of this method is that it requires separating the twoenantiomers, thereby resulting in the loss of half the product, suchthat the process cost is high.

Several stereoselective processes for the synthesis of (S)-Pregabalinhave been disclosed. For example, U.S. Pat. No. 5,599,973 discloses thepreparation of (S)-Pregabalin using stoichiometric(+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may berecycled. In general, however, that route is of limited use forscale-up, principally due to the low temperature required for thereactions, the use of pyrophoric reagent, such as, butyl lithium, toside reactions, and due to a low overall yield.

Another process is disclosed in U.S. Patent Application Publication No.2003/0212290, which discloses asymmetric hydrogenation of acyano-substituted olefin, compound 7, to produce a cyano precursor of(S)-3-(aminomethyl)-5-methyl hexanoic acid, compound 8, as seen inscheme 2.

Subsequent reduction of the nitrile in compound 8 by catalytichydrogenation produces (S)-Pregabalin. The cyano hexenoate startingmaterial, compound 7, is prepared from 2-methyl propanal andacrylonitrile (Yamamoto et al, Bull. Chem. Soc. Jap., 58, 3397 (1985)).However, the disclosed method requires carbon monoxide under highpressure, raising serious problems in adapting this scheme forproduction scale processes.

A process published by G. M. Sammis, et al., J. Am. Chem. Soc., 125(15), 4442-43 (2003), takes advantage of the asymmetric catalysis ofcyanide conjugate addition reactions. The method discloses theapplication of aluminum salen catalysts to the conjugate addition ofhydrogen cyanide to α,β-unsaturated imides as shown in scheme 3.Reportedly, TMSCN is a useful source of cyanide that can be used in theplace of HCN. Although the reaction is highly selective, this process isnot practicable for large scale production due to the use of highlypoisonous reagents. Moreover, the last reductive step requires highpressure hydrogen, which only adds to the difficulties required foradapting this scheme for a production scale process.

In 1989, Silverman reported a convenient synthesis of 3-alkyl-4-aminoacids compounds in SYNTHESIS, Vol. 12, 953-944 (1989). Using 2-alkenoicesters as a substrate, a series of GABA analogs were produced by Michaeladdition of nitromethane to α,β-unsaturated compounds, followed byhydrogenation at atmospheric pressure of the nitro compound to aminemoiety as depicted in scheme 4.

Further resolution of compound 14 may be employed to resolve Pregabalin.This, of course, results in the loss of 50 percent of the product, aserious disadvantage. However, the disclosed methodology reveals thatthe nitro compound can serve as an intermediate for the synthesis of3-alkyl-4-amino acids.

Recent studies have indicated that cinchona alkaloids are broadlyeffective in chiral organic chemistry. A range of nitroalkenes werereportedly treated with dimethyl or diethyl malonate in THF in thepresence of cinchona alkaloids to provide high enantiomeric selectivityof compound 15,

and its analogues. For example, see H. Li, et al., J. Am. Chem. Soc.,126 (32), 9906-07 (2004). These catalysts are easily accessible fromeither quinine or quinidine, and are reportedly highly efficient for asynthetically C—C bond forming asymmetric conjugate addition as shown inscheme 5.

R₃ represents several alkyl and aryl groups. The scope of the reactionhas been extended to other nitroolefins and applied to prepare ABT-546employing bis(oxazoline)Mg(OTf)₂. See, for example, D. M. Barnes, etal., J. Am. Chem. Soc., 124 (44), 13097-13105 (2002).

Other groups have investigated a new class of bifunctional catalystsbearing a thiourea moiety and an amino group on a chiral scaffold. SeeT. Okino, et al., J. Am. Chem. Soc., 127 (1), 119-125 (2005). On thebasis of a catalytic Michael addition to the nitroolefin withenantiomeric selectivity, they were able to prepare a series ofanalogues of compound 15.

Thus, there is a need in the art for new processes for the preparationof (S)-Pregabalin that does not suffer from the disadvantages mentionedabove.

SUMMARY OF THE INVENTION

In one embodiment, the invention encompasses(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-aryl-alkyl]amino}ethyl)hexanoic acid ofthe following formula 24,

wherein Ar is a C₆₋₁₀ aromatic group, and R is a straight or branchedC₁₋₄ alkyl, ester or carboxylic acid.

In another embodiment, the invention encompasses a(R)-3-isobutylpentanedioic acid amide-((S)-1-aryl-alkyl)amide of thefollowing formula 25,

wherein Ar is a C₆₋₁₀ aromatic group, and R is a straight or branchedC₁₋₄ alkyl, ester or carboxylic acid.

In another embodiment, the invention encompasses a(S)-4-methyl-2-{[((S)-1-aryl-alkyl-carbamoyl)-methyl]pentyl}carbamicacid methyl ester of the following formula 26,

wherein Ar is a C₆₋₁₀ aromatic group, and R is a straight or branchedC₁₋₄ alkyl, ester or carboxylic acid.

In another embodiment, the invention encompasses a(S)-2-carbamoylmethyl-4-methylpentyl)carbamic acid alkyl ester of thefollowing formula 27,

wherein R′ is a straight or branched C₁₋₅ alkyl.

In another embodiment, the invention encompasses a process for preparing(S)-Pregabalin comprising: preparing a compound of the following formula24

wherein Ar is a C₆₋₁₀ aromatic group and R is a straight or branchedC₁₋₄ alkyl, ester, or carboxylic acid; converting the compound offormula 24 into a compound of the following formula 25, wherein Ar is aC₆₋₁₀ aromatic group, and R is a straight or branched C₁₋₄ alkyl, ester,or carboxylic acid;

converting the compound of formula 25 into a compound of the followingformula 26

wherein Ar is a C₆₋₁₀ aromatic group, and R is a straight or branchedC₁₋₄ alkyl, ester, or carboxylic acid; converting the compound offormula 26 into a compound of the following formula 27

wherein R′ is a straight or branched C₁₋₅ alkyl; and converting thecompound of formula 27 into (S)-Pregabalin.

The compound of formula 24 is preferably prepared by a processcomprising: combining a chiral amine of the following formula 23,

wherein Ar is a C₆₋₁₀ aromatic group, and R is a straight or branchedC₁₋₄ alkyl, ester, or carboxylic acid, an organic solvent selected fromat least one of C₆₋₁₀ aromatic hydrocarbons, substituted aromatichydrocarbons, C₂₋₈ ethers, halogenated hydrocarbons, straight orbranched C₁₋₄ alcohols, C₃₋₈ esters, straight, branched or cyclic C₁₋₆alkanes, or C₃₋₈ ketones, and at least one base, to obtain a mixture;cooling the mixture to a temperature of about −70° C. to about 10° C.;adding 3-isobutyl glutaric anhydride to the mixture; maintaining themixture at a temperature of about −70° C. to about 10° C. for at leastabout one hour to obtain the compound of formula 24; and recovering thecompound of formula 24 from the mixture.

The compound of formula 24 is preferably converted into the compound offormula 25 by a process comprising: combining at a temperature of about20° C. to about −30° C., the compound of formula 24 and at least oneorganic solvent selected from the group consisting of substitutedaromatic hydrocarbons, C₆₋₁₀ aliphatic hydrocarbons, halogenatedcarbons, ethers and ketones, an amidation reagent selected from thegroup consisting of C₁₋₄ alkyl and C₆₋₈ aryl haloformates, and acidhalides, and a base to form a mixture; maintaining the mixture for aboutone hour to about two hours at a temperature of about −10° C. to about20° C.; adding ammonia to obtain the compound of formula 25; andrecovering the compound of formula 25 from the mixture.

The compound of formula 25 is preferably converted into the compound offormula 26 by a process comprising: combining a solution of the compoundof formula 25 in at least one straight or branched alkyl alcohol, suchas methyl, ethyl, isopropyl, n-butyl, isobutyl, or t-butyl alcohol,preferably, methanol or ethanol, at a temperature of about −25° C. toabout −45° C. with bromine, in the presence of at least one base, toobtain a basic mixture; warming the basic mixture to a temperature ofabout 50° C. to about 70° C., preferably, about 55° C. to about 60° C.;warming the basic mixture for about 1 hour to about 4 hours to obtainthe compound of formula 26; and recovering the compound of formula 26from the basic mixture. Preferably, the compound of formula 26 isobtained in a purity of about 90% to about 100% area by HPLC, morepreferably, in a purity of about 92% to about 100% area by HPLC, and,most preferably, in a purity of about 95% to about 100% area by HPLC.

Preferably, the base is a metal alkoxide, such as sodium ethoxide,sodium methoxide, potassium methoxide, potassium ethoxide, or potassiumtert-butoxide, and is preferably sodium ethoxide or sodium methoxide.Preferably, the compound of formula 26 is recovered by evaporating thesolvent from the basic mixture to form a residue and extracting thecompound of formula 26 from the residue. Preferably, the compound offormula 26 is extracted with dichloromethane, ethyl acetate, or toluene.The recovered compound of formula 26 is preferably crystallized from anorganic solvent selected from at least one of ethers, esters,hydrocarbons, substituted hydrocarbons, and alcohols. Preferably, theorganic solvent is diisopropyl ether, ethyl acetate, cyclohexane,dichloromethane, or methanol.

Preferably, the compound of formula 26 is converted into the compound offormula 27 by a process comprising: combining the compound of formula 26and a mixture of water and an ether to obtain a mixture; combining themixture with ammonia and an alkali metal at a temperature of about −30°C. to about −60° C., preferably, about −40° C. to about −30° C., toobtain a reaction mixture; maintaining the reaction mixture for about 4to about 10 hours until the excess of ammonia is evaporated to obtainthe compound of formula 27; and, preferably, recovering the compound offormula 27 from the reaction mixture. Preferably, the ether istetrahydrofuran or dioxane. Preferably, the ammonia is liquid ammonia.Preferably, the alkali metal is lithium or sodium. Preferably, thecompound of formula 27 is recovered by extraction, and, more preferably,the compound of formula 27 is crystallized from an ether, such asdiisopropyl ether.

Preferably, the compound of formula 27 is converted to (S)-Pregabalin ina process comprising: combining the compound of formula 27 with an acidto obtain a mixture; maintaining the mixture at a temperature of about60° C. to about 130° C., preferably, about 80° C. to about 110° C., forabout 5 to about 30 hours, preferably, for about 18 to about 30 hours,and, more preferably, for about 5 to about 10 hours, to obtain(S)-Pregabalin; and recovering the (S)-Pregabalin from the mixture.Preferably, the acid is a strong mineral acid, such as hydrochloric acidor sulfuric acid.

Preferably, the (S)-Pregabalin is recovered by a process comprising:adjusting the pH of the mixture to about 3 to about 1; extracting asolution of (S)-Pregabalin from the mixture with an alcohol; adjustingthe pH of the solution to about 4 to about 7 to induce the precipitationof (S)-Pregabalin; and recovering the precipitated (S)-Pregabalin.Preferably, the (S)-Pregabalin is obtained in a purity of at least about98% area by HPLC, and, more preferably, about 99% to about 100% area byHPLC.

In another embodiment, the invention encompasses a process for preparing(S)-Pregabalin comprising: combining a compound of the following formula26,

wherein Ar is a C₆₋₁₀ aromatic group, and R is a straight or branchedC₁₋₄ alkyl, ester, or carboxylic acid, with an acid to obtain a mixture;maintaining the mixture at a temperature of about 60° C. to about 130°C., for about 3 hours to about 30 hours, to obtain (S)-Pregabalin; andrecovering the (S)-Pregabalin from the mixture.

In another embodiment, the invention encompasses a process for recycling3-isobutyl glutaric anhydride comprising: preparing a compound offormula 24 from 3-isobutyl glutaric anhydride by the process accordingto claim 29; crystallizing the recovered compound of formula 24 from anorganic solvent; removing the crystals from the organic solvent;combining the remaining organic solvent with an acid to obtain a firstmixture; maintaining the first mixture at a temperature of about 60° C.to about 130° C., to obtain 3-isobutyl glutaric acid; combining the3-isobutyl glutaric acid with acetic anhydride to obtain a secondmixture; heating the second mixture to a temperature of about 125° C. toabout 145° C. to obtain 3-isobutyl glutaric anhydride; and recoveringthe 3-isobutyl glutaric anhydride from the second mixture.

In another embodiment, the invention encompasses (S)-pregabalin havingan enantiomeric purity of about 99% to about 100% area by HPLC,preferably of about 99.9% to about 100% area by HPLC.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates an IR spectrum of(3S)-5-methyl-3-(2-oxo-2{([(1S)-1-phenylmethyl]amino}ethyl)hexanoic acidof formula 24A.

FIG. 2 illustrates a ¹H-NMR spectrum of(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylmethyl]amino}ethyl)hexanoic acidof formula 24A.

FIG. 3 illustrates a ¹³C-NMR spectrum of(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylmethyl]amino}ethyl)hexanoic acidof formula 24A.

FIG. 4 illustrates a powder X-ray diffraction pattern of(3S)-5-methyl-3-(2-oxo-2 {[(1S)-1-phenylmethyl]amino}ethyl)hexanoic acidof formula 24A.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stereoselective synthesis of(S)-Pregabalin according to the following scheme:

This process allows for obtaining (S)-Pregabalin with a relatively highenantiomeric purity.

The invention encompasses(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-aryl-alkyl]amino}ethyl)hexanoic acidsof formula 24,

wherein Ar is a C₆₋₁₀ aromatic group and R is a straight or branchedC₁₋₄ alkyl, ester, or carboxylic acid.

Preferably, the C₆₋₁₀ aromatic group is naphthyl, phenyl, substitutedphenyl, or substituted naphthyl, more preferably phenyl. Preferably, thesubstituted phenyl is a phenyl group substituted with at least one ofalkoxy, halogen, alkyl, carboxylic acid, or ester. A preferred alkoxyphenyl is methoxyphenyl. Preferred halogenated phenyls arechlorobenzene, bromobenzene, and fluorobenzene. Preferred alkylatedphenyls are either toluene or ethylbenzene. Preferably, the carboxylicacid substituent is —COOH, —CH₂COOH, —CH(CH₃)COOH or —C(CH₃)₂COOH.Preferably the ester substituent is a methylester, ethylester,isopropylester, n-butylester, isobutyl, or t-butyl derivative of one ofthe above-listed carboxylic acid substituents.

Preferably, the C₁₋₄ alkyl is methyl, ethyl, isopropyl, n-butyl,isobutyl or t-butyl, more preferably, methyl.

When Ar is phenyl and R is methyl, the compound of formula 24 is(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylmethyl]amino}ethyl)hexanoic acid24A

which may be characterized by data selected from: a ¹³C-NMR (CDCl₃, 300MHz) spectrum having carbon chemical shifts at about 21.74, 22.19,22.66, 24.95, 29.44, 30.89, 36.73, 38.15, 40.55, 43.45, 48.92, 125.41,126.06, 127.29, 128.57, 143.01, 171.92 and 176.71 ppm; a ¹H-NMR (CDCl₃,75 MHz) spectrum having hydrogen chemical shifts at about 0.77, 1.18,1.38, 1.56, 2.22, 5.03, 6.59-6.62, 7.11-7.22 and 10.88 ppm; and an IRspectrum having peaks at about 3321.39, 2955.91, 1693.33, 1617.43,1561.07 and 698.24 cm⁻¹.

The invention also encompasses isolated(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylmethyl]amino}ethyl)hexanoic acid24A, preferably in crystalline form. The crystalline form of 24A may becharacterized by a powder X-ray diffraction pattern having peaks atabout 4.3°, 6.9°, 7.2°, and 7.7° 2θ±0.2° 2θ. The crystalline form of 24Amay be further characterized by X-ray powder diffraction peaks at about6.3°, 8.1°, 9.7°, 10.3°, 11.3°, 12.9°, 13.9°, 15.1°, 15.7°, 17.5°,18.6°, 19.1°, 20.5°, 20.9°, 21.8°, 22.3°, 23.3°, and 23.8° 2θ±0.2° 2θ.Moreover, the crystalline form of 24A may have a melting range of about95° C. to about 98° C.

The invention also encompasses isolated(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylmethyl]amino}ethyl)hexanoic acid24A having an optical purity of at least about 80% area by HPLC,preferably of at least about 93% area by HPLC, more preferably, of about98% to about 100% area by HPLC, most preferably, of about 99% to about100% area by HPLC.

The invention also encompasses (R)-3-isobutylpentanedioic acidamide-((S)-1-aryl-alkyl)amides of formula 25,

wherein Ar is a C₆₋₁₀ aromatic group, and R is a straight or branchedC₁₋₄ alkyl, ester, or carboxylic acid.

Where Ar is phenyl and R is methyl, the compound of formula 25 is(R)-3-isobutylpentanedioic acid amide-((S)-1-phenylmethyl)amide 25A.

The invention further encompasses(S)-4-methyl-2-{[((S)-1-aryl-alkyl-carbamoyl)-methyl]pentyl}carbamicacid methyl esters of formula 26,

wherein Ar and R are as defined above for formula 24.

When Ar is phenyl and R and is methyl, the compound of formula 26 is(S)-4-methyl-2-[((S)-1-aryl-alkyl-carbamoyl)-methyl]pentyl}carbamic acidmethyl ester 26A.

The invention also encompasses(S)-2-carbamoylmethyl-4-methylpentyl)carbamic acid alkyl esters offormula 27,

wherein R′ is a straight or branched C₁₋₅ alkyl, preferably, methyl.

When R′ is methyl, the compound of formula 27 is(S)-2-carbamoylmethyl-4-methylpentyl)carbamic acid methyl ester 27A.

Further, the invention encompasses a process for the preparation of(S)-Pregabalin via the intermediate compound of formula 24. The processcomprises preparing the intermediate of formula 24, converting theintermediate compound of formula 24 into the diamide of formula 25,converting the diamide of formula 25 into the chiral carbamate offormula 26, converting the chiral carbamate into the compound of formula27, and converting the compound of formula 27 into (S)-Pregabalin.Although each of the compounds of formula 24, formula 25, formula 26,and formula 27 can be isolated prior to conversion, isolation of thecompounds of formula 26 and formula 27 is not required. Therefore, oncethe compound of formula 25 has been prepared and isolated, thepreparation of the compound of formula 27 from the compound of formula25 or the compound of formula 26 and the preparation of (S)-Pregabalinfrom the compound of formula 25 or the compound of formula 26 does notrequire isolation of any of the intermediate compounds. Thus, once thecompound of formula 25 has been prepared and isolated, (S)-Pregabalincan be prepared in a one-pot process without the isolation of either ofthe compounds of formula 26 or formula 27.

The intermediate compound of formula 24 may be prepared by combining achiral amine of formula 23,

an organic solvent selected from at least one of C₆₋₁₀ aromatichydrocarbons, substituted aromatic hydrocarbons, C₂₋₈ ethers,halogenated hydrocarbons, straight or branched C₁₋₄ alcohols, C₃₋₈esters, straight, branched or cyclic C₁₋₆ alkanes, or C₃₋₈ ketones, andat least one base, to obtain a mixture, cooling the mixture, and adding3-isobutyl glutaric anhydride of formula 22

to the mixture to obtain the compound of formula 24,

which is then recovered.

The 3-isobutyl glutaric anhydride of formula 22 may be preparedaccording to the process disclosed in U.S. Pat. No. 5,616,793.

The chiral amine of formula 23 is commercially available, and is used asa chiral auxiliary is a primary amine or a chiral amino acid derivative,wherein Ar and R are as defined above for the compound of formula 24.Preferably, the chiral amine of formula 23 is methylbenzylamine, andmore preferably the chiral amine of formula 23 is (S)-methylbenzylamine.

Preferably, the aromatic group is toluene. The preferred ether isselected from tert-butyl methyl ether, tetrahydrofuran, diisopropylether, and diethyl ether. Preferably, the halogenated hydrocarbon isdichloromethane. Preferred C₁₋₄ alcohols are isopropyl alcohol, ethanol,methanol, or n-butanol. Preferably, the ester is selected from ethylacetate, isopropyl acetate, and isobutyl acetate. A preferred straight,branched or cyclic C₁₋₆ alkane is either hexane or cyclohexane.Preferred ketones are selected from acetone, methyl isobutyl ketone, andmethyl ethyl ketone. The more preferred organic solvent is toluene.

Preferably, the base is an organic base selected from diethyl amine,triethyl amine, di-n-propyl amine, di-isopropyl amine, tertbutylamine,morpholine, piperidine, pyridine, and 4-dimethyl aminopyridine. The mostpreferred base is 4-dimethyl aminopyridine.

Preferably, the mixture is cooled to a temperature of about −70° C. toabout 10° C. before adding the 3-isobutyl glutaric anhydride.Preferably, the mixture is maintained at a temperature of about −70° C.to about 10° C., more preferably of about 0° C. to about −50° C. andmost preferably of about −40° C. to −30° C., before recovering thecompound of formula 24. Preferably, the mixture is maintained for atleast about one hour, more preferably about one hour to about six hours,most preferably, about one hour to about two hours, before recoveringthe compound of formula 24.

The order of combining the reacting substances when preparing thecompound of formula 24 may influence the purity and the yield of thefinal product. Preferably, the chiral amine of formula 23 is combinedwith the base, followed by the addition of the 3-isobutylglutaricanhydride of formula 22.

The compound of formula 24 may be recovered by any method known in theart, such as extracting the organic phase with an aqueous basic solutionto convert the acidic product to a salt, and acidifying the aqueousphase with a mineral acid to obtain back the acid product.

The compound of formula 24 may optionally be further purified by acrystallization from an organic solvent selected from at least one ofesters, nitriles, ethers, C₄₋₆ straight, branched, or cyclichydrocarbons, and C₆₋₁₀ substituted aromatic hydrocarbons. A preferredester is ethyl acetate. Preferably, the nitrile is acetonitrile. Apreferred ether is methyl t-butyl ether. A preferred C₆₋₈ substitutedaromatic group is either toluene or xylene. Preferred mixtures are thatof xylene and ethyl acetate, hexane and ethyl acetate, cyclohexane andethyl acetate, and toluene and ethyl acetate. The most preferred mixtureis that of toluene and ethyl acetate.

The compound of formula 24 obtained by the above-described process hasan optical purity of at least about 80% area by HPLC, preferably of atleast about 93% area by HPLC, more preferably of about 98% to about 100%area by HPLC, and most preferably of about 99% to about 100% area byHPLC.

The recovered compound of formula 24 is then converted to the diamide offormula 25,

in a process comprising combining a mixture of the compound of formula24 and at least one organic solvent selected from substituted aromatichydrocarbons, C₆₋₁₀ aliphatic hydrocarbons, halogenated carbons, ethersand ketones, an amidation reagent selected from C₁₋₄ alkyl and C₆₋₈ arylhaloformates, and acid halides, and at least one base, and addingammonia to obtain the compound of formula 25, which is then recovered.

Preferably, the ammonia is provided in an aqueous solution, i.e.,ammonium hydroxide.

Preferably, the C₁₋₄ alkyl halo formate is a ethyl or methyl derivativeof a chloro or bromoformate. Preferably, the C₆₋₈ aryl halo formate is abenzyl chloro or bromoformate. Preferred acid halides are acetyl,pivaloyl, oxaloyl or benzoyl chlorides and bromides. The most preferredhaloformate is either ethylchloroformate or methylchloroformate. Themore preferred acid halide is acetyl, pivaloyl, oxaloyl, or benzoylchlorides. The most preferred amidation reagent is eitherethylchloroformate or methylchloroformate.

Preferably, the substituted aromatic hydrocarbon is either toluene orxylene. A preferred C₆₋₁₀ aliphatic hydrocarbon is either hexane orheptane. Preferred ketones are acetone, methyl ethyl ketone, or methylisobutyl ketone. Preferably, the ether is diethyl ether, diisopropylether, or tert-butyl methyl ether. Preferably, the halogenatedhydrocarbon is dichloromethane. The more preferred organic solvent iseither acetone or dichloromethane.

Preferably, the base is an organic base selected from diethyl amine,triethyl amine, di-n-propyl amine, di-isopropyl amine, tri-n-butylamine, morpholine, piperidine, pyridine, and 4-dimethyl aminopyridine.The preferred base is either 4-dimethyl aminopyridine or triethyl amine.

Preferably, the mixture of the compound of formula 24 and an organicsolvent is combined with the amidation reagent and the base at atemperature of about 20° C. to about −30° C., more preferably, of about−10° C. to about −20° C. Preferably, the compound of formula 24 iscompound 24A.

Preferably, the mixture is maintained at a temperature of about −10° C.to about −20° C. before the addition of ammonia. Preferably, the mixtureis maintained for about one hour to about two hours before the additionof ammonia.

The compound of formula 25 may be recovered by known methods in the art,such as, filtering and drying.

The compound of formula 25 is obtained by the above process having apurity of at least about 80% area by HPLC, more preferably of at leastabout 95% area by HPLC.

Then, the recovered compound of formula 25 is reacted with bromine in aHoffman reaction under basic conditions. The process comprises combininga solution of a compound of formula 25 in at least one straight orbranched alkyl alcohol with bromine, in a presence of at least one base,to obtain a basic mixture, and warming the basic mixture to obtain thechiral carbamate of formula 26,

which is then recovered.

Preferably the combining step is performed at a temperature of about−25° C. to about −45° C.

Preferably, the base is a metal alkoxide selected from sodium ethoxide,sodium methoxide, potassium methoxide, potassium ethoxide, and potassiumtert-butoxide. The more preferred base is either sodium ethoxide orsodium methoxide.

Preferably, the basic mixture is warmed to a temperature of about 50° C.to about 70° C., more preferably to a temperature of about 55° C. toabout 60° C.

Preferably, the straight or branched alkyl alcohol is methyl, ethyl,isopropyl, n-butyl, isobutyl, or t-butyl alcohol, more preferablymethanol or ethanol.

Preferably, the basic mixture is warmed for about 1 hour to about 4hours before recovering the compound of formula 26.

The compound of formula 26 may be recovered by evaporating the solventand further extracting with a solvent selected from dichloromethane,ethylacetate and toluene, followed by drying over a drying agent, suchas, magnesium sulfate, followed by evaporating the solvent.

The recovered compound of formula 26 may be purified by crystallizationfrom at least one of an ether, ester, hydrocarbon, substitutedhydrocarbon, or alcohol. Preferably, the compound of formula 26 iscrystallized from at least one of diisopropyl ether, ethyl acetate,cyclohexane, dichloromethane, or methanol.

The compound of formula 26 is obtained by the above process having apurity of at least about 80% area by HPLC, preferably of about 90% toabout 100%, area by HPLC, more preferably of about 92% to about 100%area by HPLC, and most preferably, of about 95% to about 100% area byHPLC.

The amide moiety of the recovered compound of formula 26 is thenconverted to a primary amide moiety, to give the compound of formula 27

in a process comprising combining the compound of formula 26 and amixture of water and an ether to obtain a mixture, combining the mixturewith ammonia and an alkali metal to obtain a reaction mixture, andevaporating the excess of ammonia to obtain the compound of formula 27.

Preferably, the mixture containing the compound of formula 26 and amixture of water and ether is combined with ammonia and an alkali metalat a temperature of about −30° C. to about −60° C., more preferably at atemperature of about −40° C. to about −30° C.

Preferably the ether is either tetrahydrofuran or dioxane.

Preferably the ammonia is liquid.

The preferred alkali metal is either lithium or sodium.

Preferably, the excess ammonia is evaporated by maintaining the reactionmixture for about 4 to about 10 hours.

The compound of formula 27 may be recovered by any known method in theart, such as, extraction and drying over anhydrous sodium sulfate.

The compound of formula 27 may optionally be purified by crystallizationfrom ether, preferably, diisopropyl ether.

The compound of formula 27 is then converted to (S)-Pregabalin in aprocess comprising combining the compound of formula 27 with an acid toobtain a mixture and recovering (S)-Pregabalin from the mixture.

Preferably, the acid is a strong mineral acid, more preferably eitherhydrochloric acid or sulfuric acid.

Preferably, the mixture is maintained at a temperature of about 60° C.to about 130° C., more preferably of about 80° C. to about 110° C.,before recovering the (S)-Pregabalin.

Preferably, the mixture is maintained for about 5 to about 30 hoursbefore recovering the (S)-Pregabalin.

Preferably, the mixture is maintained for about 18 to about 30 hours,when the mineral acid is hydrochloric acid and for about 5 to about 10hours, when the mineral acid is sulfuric acid, before recovering the(S)-Pregabalin.

(S)-Pregabalin may be recovered by adjusting the pH of the mixture toabout 3 to about 1, preferably by addition of a strong base; extractinga solution of (S)-Pregabalin from the mixture with an alcohol; adjustingthe pH of the solution to about 4 to about 7, preferably with aninorganic or an organic base, to induce the precipitation of(S)-Pregabalin; and recovering the precipitated (S)-Pregabalin.

(S)-Pregabalin obtained by the above process has at least about 80%enantiomeric purity by area HPLC, preferably at least about 93% area byHPLC, more preferably, about 98% to about 100% area by HPLC, even morepreferably, about 99% to about 100% area by HPLC, and most preferably ofabout 99.9% to about 100% area by HPLC.

In an alternative process, the chiral carbamate compound of formula 26may be converted directly to (S)-Pregabalin. The process comprisescombining the compound of formula 26 with an acid to obtain a mixtureand maintaining the obtained mixture at a temperature of about 60° C. toabout 130° C., for about 3 hours to about 30 hours, to obtain(S)-Pregabalin, which is then recovered.

Preferably, the acid is a strong mineral acid. Preferably, the strongmineral acid is selected from a group consisting of hydrochloric acid,hydrobromic acid, and sulfuric acid.

Preferably, the mixture is maintained at temperature of about 80° C. toabout 125° C.

Preferably, the mixture is maintained for about 10 to about 30 hourswhen the mineral acid is hydrochloric acid, for about 5 to about 10hours when the mineral acid is sulfuric acid, and for about 3 hours whenthe mineral acid is hydrobromic acid.

(S)-Pregabalin may be recovered by the same method described for thereaction of converting the compound of formula 27 to (S)-Pregabalin.

Further, 3-isobutyl glutaric anhydride of formula 22 can be regeneratedby a process comprising the steps of combining the filtrate obtainedfrom the crystallization process of compound of formula 24A with an acidto form a first mixture, recovering 3-isobutyl glutaric acid of thefollowing formula 28

from the first mixture, combining the 3-isobutyl glutaric acid withacetic anhydride to obtain a second mixture, and recovering 3-isobutylglutaric anhydride of formula 22 from the second mixture, which may thenbe reused.

Preferably, the acid is a strong mineral acid, more preferably either a4N to 12N hydrochloric acid or 20 percent to 80 percent sulfuric acid.

Preferably the first mixture is maintained at a temperature of about 60°C. to about 130° C. before recovering the 3-isobutyl glutaric acid.Preferably, when the mineral acid is hydrochloric acid, the firstmixture is maintained at temperature of about 100° C. to about 110° C.before recovering the 3-isobutyl glutaric acid. Preferably, when themineral acid is sulfuric acid, the first mixture is maintained at atemperature of about 60° C. to about 130° C. before recovering the3-isobutyl glutaric acid.

Preferably, the second mixture is heated to a temperature of about 125°C. to about 145° C., more preferably, of about 130° C. to about 140° C.,before recovering the 3-isobutyl glutaric anhydride.

The 3-isobutyl glutaric anhydride may be recovered by any method knownin the art, such as, distilling the excess of acetic anhydride andcooling.

In yet another embodiment, the present invention provides pharmaceuticalcompositions comprising enantiomerically pure (S)-Pregabalin and atleast one pharmaceutically acceptable excipient. Such (S)-Pregabalin hasat least about 80% enantiomeric purity, preferably of at least about 93%area by HPLC, more preferably, of about 98% to about 100% area by HPLC,even more preferably, of about 99% to about 100% area by HPLC, and mostpreferably of about 99.9% to about 100% area by HPLC. Suchpharmaceutical composition can be prepared by combining (S)-Pregabalinwith one or more excipients or adjuvants. Selection of excipients andthe amounts to use may be readily determined by the formulationscientist based upon experience and consideration of standard proceduresand reference works in the field.

Diluents increase the bulk of a solid pharmaceutical composition, andmay make a pharmaceutical dosage form containing the composition easierfor the patient and care giver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.Avicel®), microfine cellulose, lactose, starch, pregelitinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose,dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol, and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®), andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and die. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and die, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the die. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions may also be died using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, theactive ingredient and any other solid excipients are suspended in aliquid carrier such as water, vegetable oil, alcohol, polyethyleneglycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol, and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanth,and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol, and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition may alsocontain a buffer such as gluconic acid, lactic acid, citric acid oracetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodiumacetate.

Selection of excipients and the amounts used may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates, and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant, and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches, and losenges, as well as liquid syrups,suspensions, and elixirs.

The dosage form of the present invention may be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be madefrom gelatin, and, optionally, contain a plasticizer such as glycerinand sorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling can be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended, and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried, and thenscreened and/or milled to the desired particle size. The granulate maythen be tableted or other excipients may be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet, and then comminuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

In another embodiment, the present invention provides a method oftreating a patient comprising administering to a patient in need thereofa therapeutically effective amount of the above crystalline form ofO-desmethylvenlafaxine. Preferably, the patient suffers from a conditionwhich may be treated with a norepinephrine or a serotonin re-uptakeinhibitor. Such patient may be suffering from depression.

The following non-limiting examples are merely illustrative of thepreferred embodiments of the present invention, and are not to beconstrued as limiting the invention, the scope of which is defined bythe appended claims.

EXAMPLES

Chiral HPLC analysis Instrument: Waters-2487 Column: CHIRAL PACK AD-H,250 × 4.6 mm, 5 μm Mobile phase: 2% TFA in n-Hexane/Ethanol - 95/5 Flow:0.5 ml/minute Temperature: 30° C. Wavelength: 210 nm/UV visiblespectrophotometer

¹H-NMR analysis F2-Acquisition parameters Instrument dpx 300 Probhd 5 mmDual Z5 Pulprog zg TD 16384   Solvent CDCl₃ NS 8 DS 0 SWH 8992.806 HzFIDRES 0.548877 Hz AQ 0.9110004 sec RG 32  DW 55.600 μsec DE 4.50 μsecTE 300.0K D1 5 sec P1 11.35 μsec SFO1 300.1342018 MHz NUC1 1 H PL1 0 dBF2-Processing parameters SI 32768   SF 300.13000292 MHz WDW EM SSB 0 LB0.50 Hz GB 0 PC   1.4

¹³C-NMR analysis F2-Acquisition parameters Instrument dpx 300 Probhd 5mm Dual Z5 Pulprog zgdc TD 16384 Solvent CDCl₃ NS  5043 DS   0 SWH18832.393 Hz FIDRES 1.149438 Hz AQ 0.4350452 sec RG   5792.6 DW 26.550μsec DE 4.50 μsec TE 300.0K D11 0.03 sec PL12 17.8 Db Cpdprg2 waltz 16PCPD2 90.00 μsec SFO2 300.1330013 MHz NUC2 1 H PL2 0 dB D1 1 sec P1 9.4μsec DE 4.5 μsec SFO1 75.4767751 MHz NUC1 13 C PL1 0 dB F2-Processingparameters SI 16384 SF 75.4677549 MHz WDW EM SSB   0 LB 10.00 Hz GB   0PC     1.4

IR analysis KBr pellets Number of sample scans 16 Number of backgroundscans 16 Scanning parameters 4000-500 cm⁻¹ Resolution 4 Sample gain 8Mirror velocity 0.6329 Aperture 100

X-ray analysis Instrument SIEMENS “Model: D-5000 Copper radiation 1.5406A Scanning parameters 2-50° 2θ. Step scan 0.03° Step time 0.5 second

Example 1 Preparation of(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidcompound (24)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with toluene(400 ml), (S)-(−)-phenylethylamine (142.35 g, 1.1764 mole), and4-dimethylaminopyridine (0.7176 g, 0.0059 mole). The mixture was cooledto a temperature of −10° C. to −15° C., followed by addition of asolution of 3-isobutyl glutaric anhydride (100 g, 0.59 mole) in toluene(100 ml), over a period of 45-60 minutes, and stirring for additional1.5-2 hours, at a temperature of −10° C. to −15° C. The mixture was thenextracted with 10% aqueous solution of NaOH (500 ml), and the aqueousphase was washed with toluene (1×250 ml). The pH of the aqueous phasewas adjusted to 2-2.5 by adding a solution of hydrochloric acid (1-12N).The aqueous phase was further extracted with toluene (1×800 ml) at atemperature of 70-80° C. The toluene layer was washed with 10% sodiumchloride solution {700 ml) at a temperature of 70-80° C. followed bycrystallization to get 125 g (73.0% yield) of a white solid of(3S)-5-methyl-3-(2-oxo-2-{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidwith an optical purity of 99.75%, as measured by chiral HPLC.

Example 2 Preparation of(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidcompound (24)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with toluene(400 ml), (S)-(−)-phenylethylamine (38.59 g, 0.0.319 mole), and4-dimethylaminopyridine (0.358 g, 0.0029 mole). The mixture was cooledto a temperature of −40° C. to −50° C., followed by addition of asolution of 3-isobutyl glutaric anhydride (50 g, 0.294 mole) in toluene(100 ml), over a period of 45-60 minutes, and stirring for additional1.5-2 hours, at a temperature of −40° C. to −50° C. The mixture was thenextracted with 3.5-4.0% aqueous solution of NaOH (1000 ml), and theaqueous phase was washed with toluene (1×250 ml). The pH of the aqueousphase was adjusted to 2-2.5 by adding a solution of hydrochloric acid(1-12N). The aqueous phase was further extracted with ethyl acetate(1×300 ml and 1×100 ml), followed by drying the combined ethyl acetatesextracts over anhydrous sodium sulphate, and stripping off the solventsto obtain a residue. The residue was crystallized from ethyl acetate andtoluene mixture to get 60.7 g (71.0% yield) of a white solid of(3S)-5-methyl-3-(2-oxo-2-{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidwith an optical purity of 99.75%, as measured by chiral HPLC.

Example 3 Preparation of(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidcompound (24)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with toluene(1000 ml), (S)-(−)-phenylethylamine (266.9 g, 2.206 mole), and4-dimethylaminopyridine (1.79 g, 0.0147 mole). The mixture was cooled toa temperature of −40° C. to −50° C., followed by addition of a solutionof 3-isobutyl glutaric anhydride (250 g, 1.471 mole) in toluene (250ml), over a period of 45-60 minutes, and stirring for additional 1.5-2hours, at a temperature of −40° C. to −50° C. The mixture was thenextracted with 3.5-4.0% aqueous solution of NaOH (2350 ml), and theaqueous phase was washed with toluene (1×250 ml). The pH of the aqueousphase was adjusted to 2-2.5 by adding a solution of hydrochloric acid(1-12N). The aqueous phase was further extracted with ethyl acetate(1×1250 ml and 1×500 ml), followed by drying the combined ethyl acetatesextracts over anhydrous sodium sulphate, and stripping off the solventsto obtain a residue. The residue was crystallized from toluene to get344 g (80.5% yield) of a white solid of(3S)-5-methyl-3-(2-oxo-2-{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidwith an optical purity of 98.69%, as measured by chiral HPLC.

Example 4 Preparation of (R)-3-isobutylpentanedioic acidamide-((S)-1-phenylethyl)amide (25)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with methylenedichloride (1000 ml),(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidcompound (24) (200 g, 0.687 mole), and with triethylamine (7.65 g, 0.756mole), and cooled to 0°-5° C. followed by addition of ethylchloroformate (90 g, 0.825 mole). The mixture was stirred for 1-2 hoursat a temperature of 20° C. to 25° C., followed by quenching with 25%aqueous ammonia (1000 ml). The resulted slurry was filtered and washedwith water and dried to get 140 g (70.0% yield) of a white solid of(R)-3-isobutylpentanedioic acid amide-((S)-1-phenylethyl)amide offormula 25A, with a purity of 95%, as measured by HPLC.

Example 5 Preparation of (R)-3-isobutylpentanedioic acidamide-((S)-1-phenylethyl)amide (25)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with methylenedichloride (500 ml),(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl)hexanoic acidcompound (24) (100 g, 0.343 mole), and with triethylamine (41.67 g,0.412 mole), and cooled to −15° C. to −20° C. followed by addition ofethyl chloroformate (39.1 g, 0.36 mole). The mixture was stirred for 1-2hours at a temperature of −15° C. to −20° C., followed by quenching overa solution of 20% aqueous ammonia (280 ml). The dichloromethane wasdistilled out from the mass followed by filtering the resulted slurry,washed with water and dried to get 87 g (87% yield) of a white solid of(R)-3-isobutylpentanedioic acid amide-((S)-1-phenylethyl)amide offormula 25A, with a purity of 98%, as measured by HPLC.

Example 6 Preparation of (R)-3-isobutylpentanedioic acidamide-((S)-1-phenylethyl amide (25)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with methylenedichloride (125 ml),(3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acidcompound (24) (25 g, 0.086 mole), triethyl amine (10.43 g, 0.129 mole),and cooled to 0°-5° C. followed by addition of pivaloyl chloride (12.43g, 0.103 mole). The mixture was stirred for 1-2 hours at a temperatureof 20° C. to 25° C., followed by quenching with 20% aqueous ammonia (250ml). The resulted slurry was filtered and washed with water and dried toget 15.2 g (61% yield) of a white solid of (R)-3-isobutylpentanedioicacid amide-((S)-1-phenylethyl)amide of formula 25A, with a purity of95%, as measured by HPLC.

Example 7 Preparation of (R)-3-isobutylpentanedioic acidamide-((S)-1-phenylethyl amide (25)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with acetone(125 ml), (3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24) (25 g, 0.086 mole), triethyl amine (10.43 g,0.129 mole), and cooled to 0-5° C. followed by addition of pivaloylchloride (12.43 g, 0.103 mole). The mixture was stirred for 1-2 hours ata temperature of 20° C. to 25° C., followed by quenching with 20%aqueous ammonia (250 ml). The resulted slurry was filtered and washedwith water and dried to get 10.68 g (43.4% yield) of a white solid of(R)-3-isobutylpentanedioic acid amide-((S)-1-phenylethyl)amide offormula 25, with a purity of 95.4%, as measured by HPLC.

Example 8 Preparation of{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl]pentyl}carbamicacid methyl ester (26)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with methanol(1400 ml), and cooled to −40° to −45° C. followed by addition of sodiummethoxide (130 g, 2.413 mole). A solution of bromine (154.48 g, 0.965mole) in methanol (300 ml) was slowly added at about −40 to −45° C.followed by addition of (R)-3-isobutylpentanedioic acidamide-((S)-1-phenylethyl)amide, of formula 25 (140 g, 0.48 mole), inmethanol (560 ml). The mixture was gradually warmed to a temperature of0° C. and then to 55-60° C., followed by stirring for 2 to 3 hours. Thesolvent was then stripped off and water was added to the mass. Theresulted slurry was further extracted with methylene dichloride (1×500ml and 1×250 ml), followed by drying the combined methylene dichlorideextracts over anhydrous sodium sulphate, and stripping off the solventsto obtain a residue. The residue was crystallized from diisopropyl etherto get 115 g (74.2.0% yield) of a white solid of{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl]pentyl}carbamicacid methyl ester (26) with a purity of 92%, as measured by HPLC.

Example 9 Preparation of{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl]pentyl}carbamicacid methyl ester (26)

A three-necked flask equipped with an addition funnel, thermometerpocket, drying tube and a mechanical stirrer, was charged with methanol(2000 ml), and cooled to −15° to −20° C., (R)-3-isobutylpentanedioicacid amide-((S)-1-phenylethyl)amide, of formula 25 (100 g, 0.344 mole)followed by addition of sodium methoxide (74.5 g, 1.38 mole). Bromine(82.56 g, 0.516 mole) was slowly added at about −15 to −20° C. Themixture was gradually warmed to a temperature of 0° C. and then to55-60° C., followed by stirring for 2 to 3 hours. The solvent was thenstripped off and water was added to the mass. The resulted slurry wasfurther extracted with methylene dichloride (1×500 ml), followed bywashing the methylene dichloride extract with water and brine solution.The solvent was stripped off and the residue was crystallized from amixture of methylene dichloride and cyclohexane to get 95 g (85.8.0%yield) of a white solid of{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl]pentyl}carbamicacid methyl ester (26) with a purity of 93%, as measured by HPLC.

Example 10 Preparation of {(S)-2-carbamoylmethyl-4-methylpentyl)carbamicacid methyl ester (27)

A 2 l, four-necked flask, equipped with a mechanical stirrer,thermometer pocket and a liquid ammonia inlet, was charged with{(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl]pentyl}carbamicacid methyl ester (26) (25 g, 0.078 mole), tetrahydrofuran (175 ml), andwater (25 ml). The reaction mixture was cooled to −40° to −60° C. andliquid ammonia (1000 ml) was added followed by addition of small piecesof sodium metal (7.2 g). The resultant reaction mixture was stirredvigorously for 4-10 hours until the ammonia had evaporated. Water (100ml) was added to the reaction mass under N₂ atmosphere at 5°-10° C.,followed by separating the phases. The organic layer was separated anddried over anhydrous sodium sulphate and the solvent was stripped off.The residue was crystallized from diisopropyl ether to get 10.2 g (60%yield) of {(S)-2-carbamoylmethyl-4-methylpentyl)carbamic acid methylester with purity of 73% as measured by HPLC.

Example 11 Regeneration of 3-isobutylglutaric acid

A 3 l four-necked flask, equipped with a mechanical stirrer, thermometerpocket, and condenser, was charged with a residue after crystallizationof compound 24A, (250 g) from examples 1 and 2, and 70% sulfuric acid(2500 g). The reaction mixture was refluxed at 115°-125° C. for 5-10hours, and then cooled to 20°-25° C. and diluted with water. The aqueouslayer was extracted with toluene (1×1000 ml and 1×500 ml). The combinedorganic phase was extracted with 5% sodium hydroxide solution (1500 ml),and the pH of the aqueous layer was adjusted to 1.5-2 with concentratedhydrochloric acid, followed by extractions with toluene (1×600 ml and1×400 ml). The combined organic layers were dried over anhydrous sodiumsulphate and the solvent was stripped off to obtain 3-isobutyl glutaricacid (128 g) in purity of 94% as measured by GC.

3-isobutylglutaric acid is characterized by:

1. IR (KBr): 1713.27 cm⁻¹.2. ¹H NMR (CDCl3): δ 0.89-0.92 (d, 6H), 1.25 (t, 2H), 1.6-1.69 (septet,1H), 2.42 (s, 4H), 11.96 (s, 2H).

3. ¹³C NMR (CDCl₃): δ 22.39, 25.06, 28.11, 29.50, 38.45, 43.38, 179.17,203. Example 12 Converting 3-isobutylglutaric acid to 3-isobutylglutaricanhydride, compound 22

A 1 l, four-necked flask equipped with a mechanical stirrer, thermometerpocket and condenser, was charged with 3-isobutyl glutaric acid (500 g)and acetic anhydride (326 g). The reaction mixture was refluxed at135°-1450° C. for 2.5-3 hours, followed by distilling out the unreactedacetic anhydride at 147°-155° C., and then the distillation wascontinued under vacuum to ensure removal of traces of unreacted aceticanhydride. The residue was cooled to 25°-30° C. to obtain 445 g of3-isobutylglutaric anhydride.

Example 13 Preparation of (S)-Pregabalin

A 0.2 l reactor was loaded with 6N hydrochloric acid (100 ml) containingcompound 27 (12 g, 0.055 mole), and was heated to 100°-110° C. for 12-24hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amountsufficient to provide a pH of 1. The solution was then extracted with 37ml of iso-butanol, the organic layer was separated, and Bu₃N was addedin an amount sufficient to provide a pH of 4. The (S)-Pregabalin wasprecipitated, filtered, and washed with 10 ml of iso-butanol. Afterdrying at 55° C. under vacuum, (S)-Pregabalin was obtained as whitecrystals in a 21.5% yield. Purity: 99.9% area by HPLC.

Example 14 Preparation of (S)-Pregabalin

A 0.2 l reactor was loaded with 70% sulfuric acid (200 g) containingcompound 26 (10 g, 0.031 mole), and was heated to 115-120° C. for 5-10hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amountsufficient to provide a pH of 1. The solution was then extracted with 35ml of iso-butanol, the organic layer was separated, and Bu₃N was addedin an amount sufficient to provide a pH of 4. The (S)-Pregabalin wasprecipitated, filtered, and washed with 10 ml of iso-butanol. Afterdrying at 55° C. under vacuum, (S)-Pregabalin was obtained as whitecrystals in a 40.4% yield. Purity: 99.95% area by HPLC.

Example 15 Preparation of (S)-Pregabalin

A 0.2 l reactor was loaded with 70% sulfuric acid (200 g) containingcompound 26 (10 g, 0.031 mole), and was heated to 115-120° C. for 5-10hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amountsufficient to provide a pH of 1. The solution was then extracted with 50ml of isopropanol, the organic layer was separated, and NH₄OH was addedin an amount sufficient to provide a pH of 4. The (S)-Pregabalin wasprecipitated, filtered, and washed with 10 ml of isobutanol. Afterdrying at 55° C. under vacuum, (S)-Pregabalin was obtained as whitecrystals in a 50.4% yield. Purity: 99.05% area by HPLC.

Example 16 Preparation of (S)-Pregabalin

A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26(6 g), and then was heated to reflux for 3 hours. The solution wascooled to room temperature, and water (12 ml) was added. An aqueous 47%sodium hydroxide solution was added to obtain pH of 3. The solution wasthen extracted twice with isobutanol (15 ml), the combined organiclayers were evaporated and fresh isobutanol was added (15 ml). Bu₃N (3.8g) was added. The mixture was cooled to 2° C. for 1 hour, then(S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml).After drying at 55° C. under vacuum, (S)-Pregabalin was obtained aswhite crystals in a 90% yield.

Example 17 Preparation of (S)-Pregabalin

A flask was loaded with 47% HBr (30 ml), water (15 ml), and compound 26(15 g), and then was heated to reflux for 3 hours. The solution wascooled to room temperature and water (30 ml) was added. An aqueous 47%sodium hydroxide solution was added to obtain pH of 3. The solution wasthen extracted twice with iso-butanol (37.5 ml). The organic layers werecombined and Bu₃N (9.5 g) was added. The mixture was cooled to 2° C. for1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol(10 ml). After drying at 55° C. under vacuum, (S)-Pregabalin wasobtained as white crystals in a 51% yield.

While it is apparent that the invention disclosed herein is wellcalculated to fulfill the objects stated above, it will be appreciatedthat numerous modifications and embodiments may be devised by thoseskilled in the art. Therefore, it is intended that the appended claimscover all such modifications and embodiments as falling within the truespirit and scope of the present invention.

1-24. (canceled)
 25. A (S)-2-carbamoylmethyl-4-methylpentyl)carbamicacid alkyl ester of the following formula 27,

wherein R′ is a straight or branched C₁₋₅ alkyl.
 26. The(S)-2-carbamoylmethyl-4-methylpentyl)carbamic acid alkyl ester of claim25, wherein R′ is methyl. 27-77. (canceled)